Cytosine arabinoside (ara-C) is a component of many protocols for the treatment of acute leukaemia and non-Hodgkin lymphomas in humans. The aim of the study was to prospectively evaluate the efficacy of ara-C in a myeloablative regimen in a cohort of canine lymphomas with bone marrow involvement. Seventeen dogs were enrolled. Eight were treated with a VCAA-based protocol (Group 1) and nine with the same regimen added with ara-C (Group 2). Ara-C was administered on a 5-day schedule as an i.v. continuous infusion at the dose of 150 mg m−2 per day for five consecutive days. During treatment complete remission (CR) was achieved in two dogs in Group 1 and in eight dogs in Group 2. CR rate was significantly higher in Group 2 (P < 0.01). Median survival was 72.5 days (range 6–174) in Group 1 and 243 days (range 73–635) in Group 2. Survival was significantly longer in Group 2 (P < 0.001). Both protocols were well tolerated, with a low incidence of adverse events. Ara-C added to a VCAA-based protocol appears to be safe and beneficial in dogs with stage V lymphoma. Incorporation of the nucleoside analogue might be crucial for the development of future therapeutic strategies in dogs.